Epidemiologic evidence suggests that sub-optimal nutrition during foetal and/or postnatal development influence diabetes risk later in life. In addition, such environmentally-induced phenotypes may manifest in subsequent generations, even when the environmental triggers are not present anymore. Genomes may integrate nutritional variation into permanent changes in gene expression through epigenetic modifications, including DNA methylation and histone modifications. While epigenetic mechanisms have been widely studied in other ageing related disorders like cancer, little is known regarding the potential interplay between a) nutrition, b) mammalian development, c) epigenetic mechanisms and d) metabolic disorders, such as diabetes.

We have developed a mouse model of intergenerational epigenetic inheritance of diabetes by manipulating nutrition of the parental cohort during development. Specifically, here we show that, in mice, overfeeding during early postnatal life programs adult obesity, insulin resistance and glucose intolerance in males. Furthermore, we show, for the first time, that offspring and grand-offspring from neonatally over nourished male mice also develop glucose intolerance by age 5-6 months. Across generation transmission of diabetic phenotype through the male lineage clearly suggests that the phenotype is transmitted through the gametes, likely due to epigenetic modifications. Clearly, our data suggest that nutritional challenges during critical periods of growth (i.e. foetal growth and early neonatal growth) may have metabolic consequences well beyond life span of affected individuals and manifest in subsequent generations.

These studies will provide new insights into the mechanisms and dynamics underlying epigenetic inheritance of disease, with special emphasis on diabetes.